Physiological parameters of the cardiovascular system, such as blood pressure, temperature and gas concentration are important since they provide essential information concerning the state of health of organs and the patient. Currently, dynamic blood pressure measurements are mainly performed by catheterization, consisting of a pressure-sensing catheter that is inserted into the heart chamber or blood vessel, or by Doppler echocardiography using the simplified Bernoulli equation (Burton C. Physiology and biophysics of the circulation. 2nd edition. Chicago, 1972). The first method is accompanied by the disadvantages of an invasive procedure, i.e. creating pain and risk of infection. The second, noninvasive method does not provide reliable or reproducible blood pressure values (Strauss A L, Roth F J, Rieger H. “Noninvasive assessment of pressure gradients across iliac artery stenoses: duplex and catheter correlative study” J Ultras Med 1993; 12: 17-22).
Alternative techniques are described in the literature and are mainly based on the interaction of ultrasound waves with individual gas bubbles (Fairbank W, Scully M. “A new noninvasive technique for cardiac pressure measurement: resonant scattering of ultrasound from bubbles” IEEE Trans Biomed Eng 1977; 24: 107-110; Hök B. “A new approach to noninvasive manometry: interaction between ultrasound and bubbles” Med Biol Eng Comput 1981; 19: 35-39; Tickner E G. “Precision microbubbles for right side intracardiac pressure and flow measurements” Meltzer RS and Roelandt JTCR, ed. Contrast echocardiography; London: Martinus Nijhoff, 1982; 15: 313-324; Ishihara K et al. “New approach to noninvasive manometry based on pressure dependent resonant shift of elastic microcapsules in ultrasonic frequency characteristics” Jap J App Phys 1988; 27: 125-127; DE 29 46 662 A1 (Siemens AG); EP 0 296 189 B (Schering AG); U.S. Pat. No. 4,483,345 (Miwa).
Due to the high compressibility of gas, the size of a gas bubble changes as a function of the local hydrostatic pressure. This change in size affects the acoustic characteristics of the gas bubble, like resonance frequency, scattering and attenuation cross-section, etc. Therefore, the local pressure in a fluid-filled cavity can be derived from these acoustic characteristics.
Recent attempts to utilize gas bubbles to noninvasivaly assess the pressure in fluid filled cavities (De Jong et al. WO 98/32378 (Andaris Ltd.); Shi et al. WO 99/47045) have been hampered by inaccuracy and insensitivity
De Jong et al. WO 98/32378 (Andaris Ltd.) and Bouakaz et al. (“Noninvasive measurement of the hydrostatic pressure in a fluid-filled cavity based on the disappearance time of micrometer-sized free gas bubbles” Ultrasound in Medicine and Biology 1999; 25: 1407-1415) disclosed a method for noninvasive measurement of the local pressure involving injection of what are referred to as gas containing microcapsules into the circulatory system. By transmitting a low frequency, high amplitude ultrasound burst, free-gas bubbles are released from the gas containing microcapsules into the region where the local pressure is to be measured. The disappearance time of the released free gas depends on the local pressure and is used for noninvasive determination of the local pressure. In this application, the total response of the released gas bubbles (fundamental and second harmonic) is used to calculate the disappearance time. The Bouakaz article stated that this method is inaccurate for detecting small pressure changes on the order of 5-10 mmHg, which are clinically relevant (Bouakaz et al. “Noninvasive measurement of the hydrostatic pressure in a fluid-filled cavity based on the disappearance time of micrometer-sized free gas bubbles” Ultrasound in Medicine and Biology 1999; 25: 1407-1415).
Shi et al. WO 99/47045, stated that an excellent correlation exists between the amplitude of subharmonic signals generated by microbubbles and the local pressure. Thus, they suggested that sub and ultraharmonic amplitude may be used to noninvasivaly to estimate the local pressure, asserting that subharmonic amplitudes are a much better indicator of pressure variation than fundamental and second harmonic amplitudes. However, the difference in sub- and/or ultraharmonic amplitude is very small for pressure changes ranging from 5-10 mmHg (Shi et al. “Pressure dependence of subharmonic signals from contrast microbubbles” Ultrasound in Medicine and Biology 1999; 25: 275-283). Therefore, this method is also lacking sensitivity when detecting small pressure changes. Secondly, this method strongly depends on the size of the bubbles at the location where the pressure is to be measured. In the method disclosed in WO99/47045, after injection of the bubbles the size distribution will change due to lung filtration and microbubble uptake. Therefore, the exact size of the bubbles, and consequently the acoustic characteristics like sub- and ultraharmonic-response, at the location of interest is unknown.
It is an object of the present invention to provide a new method for accurate and sensitive, noninvasive measurement of the local physical parameters in a fluid-filled cavity. With this new method small pressure changes (5-10 mmHg) can be measured, which is the main limitation of the methods described by aforementioned references. Additionally, unlike the method disclosed in WO99/47045, in the present method, the size of the bubbles at the location where the pressure is to be measured can be better controlled and, therefore, the acoustic characteristics of the bubbles at the site of interest are better specified, which makes the present invention more accurate. With reference to WO98/32378, the present invention entails shorter acquisition time, which makes it more efficient and more useful in the clinic.
This new method can provide clinicians with a valuable tool for determining the state of health of an organ without the risk of infection and with minimal patient discomfort. Moreover, it will be readily apparent to those skilled in the art that the present invention can be used as a general technique for remotely sensing physical parameters, for example in situations where direct measurement is impossible or too dangerous.